NM_020436.5:c.2640G>C

Variant names:

• chr20-51788963-C-G
• rs17802735
• NM_020436.5:c.2640G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020436.5(SALL4):​c.2640G>C​(p.Ser880Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,614,150 control chromosomes in the GnomAD database, including 12,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S880S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.088 (811 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11464 hom.)
• Consequence: SALL4 NM_020436.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.38
• Publications: 9 publications found

Genes affected

SALL4 (HGNC:15924): (spalt like transcription factor 4) This gene encodes a zinc finger transcription factor thought to play a role in the development of abducens motor neurons. Defects in this gene are a cause of Duane-radial ray syndrome (DRRS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

SALL4 Gene-Disease associations (from GenCC):

• Duane-radial ray syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Duane retraction syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• IVIC syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 20-51788963-C-G is Benign according to our data. Variant chr20-51788963-C-G is described in ClinVar as Benign. ClinVar VariationId is 261263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020436.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL4	NM_020436.5	MANE Select	c.2640G>C	p.Ser880Ser	synonymous	Exon 3 of 4	NP_065169.1
	SALL4	NM_001318031.2		c.1329G>C	p.Ser443Ser	synonymous	Exon 3 of 4	NP_001304960.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL4	ENST00000217086.9	TSL:1 MANE Select	c.2640G>C	p.Ser880Ser	synonymous	Exon 3 of 4	ENSP00000217086.4
	SALL4	ENST00000395997.3	TSL:1	c.1329G>C	p.Ser443Ser	synonymous	Exon 3 of 4	ENSP00000379319.3
	SALL4	ENST00000371539.7	TSL:1	c.309G>C	p.Ser103Ser	synonymous	Exon 2 of 3	ENSP00000360594.3

Frequencies

GnomAD3 genomes AF: 0.0877 AC: 13341 AN: 152168 Hom.: 811 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.0809

Gnomad ASJ AF: 0.0698

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.0740

GnomAD2 exomes AF: 0.0916 AC: 23021 AN: 251444 AF XY: 0.0945

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0750

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.0945

GnomAD4 exome AF: 0.120 AC: 175852 AN: 1461864 Hom.: 11464 Cov.: 32 AF XY: 0.119 AC XY: 86581 AN XY: 727234

African (AFR) AF: 0.0184 AC: 617 AN: 33480

American (AMR) AF: 0.0515 AC: 2303 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 1918 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0770 AC: 6646 AN: 86258

European-Finnish (FIN) AF: 0.108 AC: 5748 AN: 53420

Middle Eastern (MID) AF: 0.0813 AC: 469 AN: 5768

European-Non Finnish (NFE) AF: 0.137 AC: 151840 AN: 1111984

Other (OTH) AF: 0.104 AC: 6297 AN: 60396

GnomAD4 genome AF: 0.0876 AC: 13339 AN: 152286 Hom.: 811 Cov.: 32 AF XY: 0.0863 AC XY: 6426 AN XY: 74466

African (AFR) AF: 0.0226 AC: 939 AN: 41570

American (AMR) AF: 0.0808 AC: 1236 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0698 AC: 242 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5178

South Asian (SAS) AF: 0.0698 AC: 337 AN: 4830

European-Finnish (FIN) AF: 0.108 AC: 1147 AN: 10606

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9109 AN: 68022

Other (OTH) AF: 0.0733 AC: 155 AN: 2116

Alfa AF: 0.0916 Hom.: 294

Bravo AF: 0.0812

EpiCase AF: 0.129

EpiControl AF: 0.126

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Duane-radial ray syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.011
DANN	Benign	0.55
PhyloP100		-5.4
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17802735; hg19: chr20-50405502;